Background Studies on the association between adult asthma and dementia are few. We investigated the risk of dementia in patients diagnosed with adult asthma compared with that of people without asthma who were age and sex matched to the study patients.
Methods We used data from the National Health Insurance Research Database. A total of 12 771 patients with newly diagnosed asthma between 2001 and 2003 were evaluated and 51 084 people without asthma were used as the comparison cohort. Cox proportional hazard regression analysis was used to measure the HR of dementia for the asthmatic cohort, compared with that of the non-asthmatic cohort.
Results The HR of dementia was 1.27 (95% confidence interval (CI) 1.15 to 1.41) for the asthmatic cohort, compared with the non-asthmatic cohort after adjusting for age, sex, comorbidities, annual outpatient department visits and medicine used. The HR of dementia development increased substantially as frequency of asthma exacerbation and hospitalisation increased.
Conclusions This nationwide cohort study suggests that the risk of dementia development is significantly increased in patients with asthma compared with that of the general population. In addition, dementia risk increases substantially with asthma exacerbation and hospitalisation frequency increases.
- Cohort studies
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Asthma is a severe public health problem that affects more than 300 million people worldwide, and its prevalence has increased dramatically in the past few decades.1 ,2 Asthma is a chronic inflammatory disorder of the airways caused by a combination of environmental and genetic factors, which subsequently results in increased contractibility of the surrounding smooth muscle and worsened pulmonary function.3 Consequently, asthmatic patients may experience recurrent episodes of shortness of breath, chest tightness, coughing and wheezing. Moreover, patients with asthma exhibit high rates of depression and anxiety disorder, which may be associated with impaired cognition function.4–6 Although various symptomatic treatments exist, asthma currently has no cure.
Dementia is a common neurodegenerative disorder that develops in later life and involves a considerable loss of global cognitive ability to the extent that personal daily activities cannot be perform to the level that might be expected from normal ageing. Several risk factors are associated with dementia, including ageing, socioeconomic status, hypertension, hypercholesterolaemia, diabetes and head injury.7–9
Several previous studies have addressed the association between poor pulmonary function and cognition impairment.10–13 Poor performance in the measurement of forced expiratory volume in 1 second, a method used for assessing asthma, has been reported to be a risk factor for late-life cognitive impairment.10 ,14 In addition, a population-based longitudinal study on Swedish women suggested that better respiratory function in mid-life was associated with a lower late-life risk of both dementia and Alzeheimer's disease development.15 Conversely, asthmatic patients may improve cognitive functions after receiving appropriate therapy.16 ,17 Thus far, only one cohort study, conducted in Sweden, has addressed the direct association between asthma and dementia.18 Therefore, we conducted this longitudinal nationwide population-based study to investigate whether asthma increases the risk of dementia.
The Longitudinal Health Insurance Database (LHID) contains information on one million insurants randomly selected from the 2000 Registry for Beneficiaries of the National Health Insurance Research Database (NHIRD) established by the Taiwan Bureau of National Health Insurance (BNHI). The NHIRD covered 96.16% of the population of Taiwan in 2000 (http://www.nhi.gov.tw) and contains all medical records, including outpatient and inpatient claims from 1996 to 2011. The accuracy and validity of diagnoses recorded in the NHIRD were evaluated by Cheng et al.19 The identification of insurants was decoded by the NHIRD and the Institutional Review Board of China Medical University Hospital approved this study (CMU-REC-101-012). In the NHIRD, the definition of each disease is based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).
Patients newly diagnosed with asthma (ICD-9-CM 493) from 2001 to 2003 were identified in the LHID. The index date was defined as the date for asthma diagnosis. Asthma patients with history of dementia (ICD-9-CM 290.0-290.4, 294.1, and 331.0) before the index date were excluded. For each identified asthmatic cases, four people with no history of asthma or dementia were randomly selected, frequency matched by age, sex and index years, as the comparison group. All the study participants were followed up from the index date to the date dementia occurred, until they withdrew from the National Health Insurance (NHI) programme, or to the end of 2011, depending on which occurred first. The baseline comorbidities considered in this study were atrial fibrillation (AF), hypertension, diabetes, hyperlipidaemia, heart failure, stroke, head injury, annual outpatient department (OPD) visits, inhaled corticosteroids (ICS) and oral corticosteroids.
A χ2 test and t test were used to determine the difference in categorical and continuous variables between the two cohorts. The incidence (per 1000 Person-years) of dementia was calculated for both cohorts. The risk of dementia and dementia-associated risk factors were estimated using Cox proportional hazard regression. The multivariable model was adjusted for age, sex, AF, hypertension, hyperlipidaemia, diabetes, heart failure, stroke, head injury, annual OPD visits and ICSs used, which differed significantly from the crude model. We also assessed the joint effect of asthma and the two most commonly reported comorbidities on dementia risk. Because a few patients with AF were included in this study, we replaced AF with head injury. The relationship between dementia and the annual number of asthma-related visits and admissions to the emergency room (ER) was also assessed using Cox proportional hazard regression. Kaplan-Meier analysis was used to plot the cumulative incidence for dementia and a log-rank test was used to test the differences between the two cohorts.
All 63 855 participants, including 12 771 asthma patients and 51 084 people in the comparison group, were used in this retrospective cohort study. In the asthma cohort, the number of women was greater than the number of men (54.2% vs 45.8%), and the average age was 53.8 years (SD=17.3). Compared with the comparison cohort, the asthma patients were more likely to suffer from comorbidities, including AF, hypertension, diabetes, hyperlipidaemia, heart failure, stroke and head injury. In addition, the asthma patients were visiting OPD more frequently, and taking more ICS and oral corticosteroids than the comparison cohort (table 1). After 11 years of follow-up, the cumulative dementia incidence in the asthma cohort was approximately 1% higher than that of the comparison cohort (p<0.0001, figure 1).
Patients with asthma had a 1.22-fold higher incidence of dementia than that of the comparison cohort (5.13 vs 4.20 per 1000 Person-years, table 2). After the data were adjusted for age, sex, comorbidities, annual OPD visits and oral corticosteroids used, the asthmatic patients exhibited a 1.27-fold greater risk (95% CI 1.15 to 1.41) of dementia development compared with that of the comparison cohort. The men had a higher incidence of dementia than that of the women (4.78 vs 4.08 per 1000 Person-years), but the dementia risk was lower than that of women after controlling for age, comorbidities, annual OPD visits and oral corticosteroids (HR=0.90, 95% CI 0.83 to 0.97). Elderly people had an 11.1-fold higher risk than that of younger people (95% CI 9.86 to 12.5). Patients with stroke had the highest risk of dementia (HR=1.59, 95% CI 1.39 to 1.81), followed by AF (HR=1.50), those with more than 30 annual OPD visits (HR=1.43), head injury (HR=1.31), diabetes (HR=1.26), hypertension (HR=1.16) and hyperlipidaemia (HR=1.13) in the multivariable model. In addition, patients taking ICS had a significantly lower risk of dementia in the same multivariable model.
Table 3 presents the joint effect of asthma, stroke and head injury on dementia risk. Compared with the patients without asthma, stroke or head injury; the dementia risk of patients with these 3 comorbidities increased by 167% and that of patients presenting with any 2 comorbidities increased by approximately 80%. Patients with only stroke, head injury or asthma had a 1.70-, 1.30-, and 1.27-fold risk, respectively, compared with that of patients without asthma, stroke and head injury.
The association between dementia and annual ER visits and admissions for asthma is presented in table 4. Compared with the comparison cohort, the risk increased as the number of ER visits, admissions or combined ER visits and admissions for asthma increased, from 1.25 to 20.9, 1.23 to 5.57 and 1.22 to 6.18, respectively.
In this longitudinal population-based cohort study, we observed that patients with asthma have an increased risk of developing dementia in the subsequent 11 years. Asthmatic patients have a 1.27-fold increased risk of dementia development compared with that of the general population, after adjusting for age, sex and comorbidities. Few studies have explored the association between asthma and dementia, and the findings are inconsistent. Caldera-Alvarado et al13 conducted a cross-sectional study with generally healthy participants older than 55 years, and observed a 78% increased risk of mild cognition impairment in the patients with asthma. However, a longitudinal population-based study in Sweden, examining the association between atopic disorders including asthma and Alzheimer's disease or any dementia, fail to find that asthma increases the subsequent risk of Alzheimer's disease (HR: 0.80, 95% CI 0.51 to 1.25) and dementia (HR:0.87, 95% CI 0.61 to 1.26), which is not in line with our study results. The possible explanations for this discrepancy might be attributable to the exposure assessment in that study being based on self-report instead of physician's diagnosis, which makes it not as reliable as ours; and also the different covariates adjusted for in each study.18
Although the specific mechanisms underlying the association between asthma and dementia are unclear, several potential shared risks and pathogenic factors may contribute to the increased risk of dementia in asthma patients. Asthma is a chronic inflammatory disorder of the airways, which involves an array of inflammatory cells and cytokines. Similarly, inflammation in the central nervous system has been demonstrated to play a crucial role in the pathogenesis of AD, which accounts for more than two-thirds of all dementia cases.20 Dunn et al21 observed that episodes of infection can increase the risk of dementia in elderly patients (age >84 years) in a nested case–control study. Recently, evidence from animal studies has indicated that respiratory inflammation with Bordetella pertussis increases glial activation and amyloid-β deposition in mice brains.22 The aforementioned evidence implies that infections that occur outside the brain and alterations in the peripheral immune system might be critical factors in the progression of AD. Finally, in asthmatic patients, the lung structure is remodelled because of persistent inflammation, which obstructs the peripheral airway and leads to hypoxic conditions in the affected lung region. Chronic hypoxia may subsequently lead to the abnormal synthesis of neurotransmitters, oxidative stress and blood-brain barrier dysfunction, all of which may be involved in the aetiology of dementia.23–25
It is well known that dementia is usually an underdiagnosed health problem,26 therefore, people with more healthcare utilisations might have a greater chance to have a diagnosis of dementia. In addition, evidence has shown that corticosteroid use may lead to or accelerate hippocampal atrophy, and thus might increase dementia risk.27 ,28 In our study, asthmatic patients have significantly higher annual OPD visits and oral corticosteroid use than the comparisons. However, asthma was still an independent risk factor for dementia development after adjusting for annual OPD visits, oral corticosteroid use and other confounding factors.
Interestingly, our data exhibit that patients taking ICS for asthma control have a significantly lower dementia risk compared with those without inhaled medications. We speculate that this lower risk might be associated with the improvement of asthma control by ICS. This hypothesis is supported by the study by Bozek et al17, who reported that 1 year of antiasthmatic therapy in the form of metered dose inhaler significantly improves the cognitive functions in elderly asthmatic patients. However, further investigations are required to corroborate this finding.
In this study, the men exhibited a higher incidence rate of dementia than did the women. However, the men exhibited a significantly lower adjusted HR of dementia development than the women did after controlling for age and comorbidities. Because no comparable studies exist, future studies may be also required to corroborate or refute these findings.
The incidence rate of dementia was significantly higher in people older than 65 years than in those aged between 20 and 64 years; the risk of dementia was also significantly higher after adjusting for covariates. This finding is compatible with that of previous studies, which suggest that age is one of the strongest risk factors for dementia.29 ,30
The Global Initiative for Asthma recommended that asthma severity be classified based on the intensity of treatment required to achieve effective asthma control.1 Therefore, we evaluated the severity of asthma according to episodes of acute exacerbation involving ER visits and hospital admissions. Our data indicated that the risk of dementia increases with the number of asthma-related ER visits and admissions. Thus far, no study has investigated the relationship between asthma exacerbation and the risk of dementia development. This dose–response relationship between asthma severity and dementia risk further strengthened our main finding that asthma increases the subsequent risk of dementia development.
This investigation was a nationwide population-based cohort longitudinal study on the risk of dementia development in people with asthma. These findings can be generalised; however, several limitations should be considered. First, all study data retrieved from NHIRD were deidentified secondary data that were released to the public for research purposes. Therefore, detailed information on the lifestyles of the patients was not provided, such as education level, occupation, exercise, diet and cigarette smoking, all of which are potential confounding factors. Second, the evidence derived from a retrospective cohort study is generally weaker than that from randomised trials because of potential bias related to adjustments for confounding factors. Bias might still exist despite our meticulous study design. Nevertheless, in the NHI programme from which the NHIRD is derived, all the insurance claims must be reviewed and scrutinised by medical reimbursement specialists. Therefore, the findings regarding the relationship between asthma and dementia remained highly reliable because of the validity of the database, large sample size and long follow-up period used in this study.
In conclusion, we determined that people with asthma were at higher risk of subsequent dementia development than were people without asthma within an 11-year follow-up period. This effect is particularly prominent in people older than 65 years. Further study is advised to confirm our findings and explore the underlying pathomechanisms.
What is already known on this subject?
Asthma and dementia are common disorders.
Studies on the association between adult asthma and dementia are few.
What this study adds?
This nationwide cohort study suggests that the risk of dementia development is significantly increased in patients with asthma.
Dementia risk increases significantly as asthma exacerbation and hospitalisation frequency increases.
Y-HP and B-RW contributed equally.
Contributors Y-HP, B-RW and C-HK were involved in conception and design. C-HK was involved in administrative support. All authors were involved in collection and assembly of data. Y-HP, B-RW, C-HM and C-HK were involved in data analysis and interpretation. All authors were involved in manuscript writing and final approval of the manuscript. C-HK gave final approval to the version to be published and was involved in critical writing or revising of the intellectual content: C-HK.
Funding This work was supported by the study projects (CMU102-BC-2) in China Medical University; Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-B-212-113002); Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW103-TD-B-111-03, Taiwan).
Competing interests None.
Ethics approval The Institutional Review Board of China Medical University Hospital approved this study (CMU-REC-101-012).
Provenance and peer review Not commissioned; externally peer reviewed.